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Combinatorial Chemistry & High Throughput Screening

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ISSN (Print): 1386-2073
ISSN (Online): 1875-5402

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Research Article

TIGIT as a Novel Prognostic Marker for Immune Infiltration in Invasive Breast Cancer

Author(s): Chenming Guo, Zhiwen Luo, Dilimulati Ismtula, Xiaojuan Bi, Han Kong, Yiyang Wang, Zhen Yang and Xinmin Mao*

Volume 26, Issue 3, 2023

Published on: 15 August, 2022

Page: [639 - 651] Pages: 13

DOI: 10.2174/1386207325666220629162823

open access plus

Abstract

Background: To assess the levels and potential therapeutic and prognostic significance of TIGIT in invasive breast cancer.

Methods: The Cancer Genome Atlas database was used to evaluate TIGIT levels in invasive breast cancer and its association with clinicopathological features. Immunohistochemistry (IHC) was performed to validate it. Further, the Kaplan-Meier survival curve, univariate and multivariate Cox regression models were applied in analyzing the role of TIGIT in the prognosis of invasive breast cancer. Go / KEGG enrichment analyses techniques were used to investigate the possible cellular mechanism, and string database was used to explore TIGIT-related proteins. Finally, the TIMER database was used to determine the association between TIGIT and immune cell infiltrations.

Results: TIGIT was differentially expressed in Pan cancer tissues compared with normal tissues. Relative to normal tissues, TIGIT levels in invasive breast cancer were elevated (p<0.05). TIGIT mRNA level was significantly different from T stage, age, ER and PR level (p<0.05). The high levels of TIGIT exhibited positive correlations with PFI and OS (p<0.05). Univariate analysis revealed that age, clinical stage, high TNM stage, menopausal status and radiotherapy were the factors affecting OS (p< 0.05). Multivariate analysis revealed that age, high clinical stage and menopausal status were independent risk factors for tumor progression (p<0.05). CD226, INPP5D, PVR, PVRL2 and PVRL3 proteins interact with TIGIT. The TIGIT levels were significantly correlated with infiltrations of immune cells (such as CD8+ T cells) (r=0.917, p<0.05).

Conclusion: TIGIT is elevated in invasive breast tumor and is closely associated with the prognosis of invasive breast cancer. TIGIT may be the target of immunotherapy for invasive breast cancer.

Keywords: TIGIT, invasive breast cancer, immune checkpoint, prognosis, bioinformatics analysis, tumor immunity.

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[1]
Guidelines for clinical diagnosis and treatment of advanced breast cancer in China (2020 Edition). Chinese J. Oncol., 2020, 42(10), 781-797.
[2]
Harbeck, N.; Penault-Llorca, F.; Cortes, J.; Gnant, M.; Houssami, N.; Poortmans, P.; Ruddy, K.; Tsang, J.; Cardoso, F. Breast cancer. Nat. Rev. Dis. Primers, 2019, 5(1), 66.
[http://dx.doi.org/10.1038/s41572-019-0111-2] [PMID: 31548545]
[3]
Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global cancer statistics 2020: GLOBOCAN esti-mates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin., 2021, 71(3), 209-249.
[http://dx.doi.org/10.3322/caac.21660] [PMID: 33538338]
[4]
Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of inci-dence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin., 2018, 68(6), 394-424.
[http://dx.doi.org/10.3322/caac.21492] [PMID: 30207593]
[5]
Adams, S.; Loi, S.; Toppmeyer, D.; Cescon, D.W.; De Laurentiis, M.; Nanda, R.; Winer, E.P.; Mukai, H.; Tamura, K.; Armstrong, A.; Liu, M.C.; Iwata, H.; Ryvo, L.; Wimberger, P.; Rugo, H.S.; Tan, A.R.; Jia, L.; Ding, Y.; Karantza, V.; Schmid, P. Pembrolizumab monotherapy for previously untreated, PD-L1-positive, metastatic triple-negative breast cancer: Cohort B of the phase II KEYNOTE-086 study. Ann. Oncol., 2019, 30(3), 405-411.
[http://dx.doi.org/10.1093/annonc/mdy518] [PMID: 30475947]
[6]
Yu, X.; Harden, K.; Gonzalez, L.C.; Francesco, M.; Chiang, E.; Irving, B.; Tom, I.; Ivelja, S.; Refino, C.J.; Clark, H.; Eaton, D.; Grogan, J.L. The surface protein TIGIT suppresses T cell activation by promoting the generation of mature immunoregulatory dendritic cells. Nat. Immunol., 2009, 10(1), 48-57.
[http://dx.doi.org/10.1038/ni.1674] [PMID: 19011627]
[7]
Kong, Y.; Zhu, L.; Schell, T.D.; Zhang, J.; Claxton, D.F.; Ehmann, W.C.; Rybka, W.B.; George, M.R.; Zeng, H.; Zheng, H. T-Cell immuno-globulin and ITIM domain (TIGIT) associates with CD8+ T-cell exhaustion and poor clinical outcome in aml patients. Clin. Cancer Res., 2016, 22(12), 3057-3066.
[http://dx.doi.org/10.1158/1078-0432.CCR-15-2626] [PMID: 26763253]
[8]
Johnston, R.J.; Comps-Agrar, L.; Hackney, J.; Yu, X.; Huseni, M.; Yang, Y.; Park, S.; Javinal, V.; Chiu, H.; Irving, B.; Eaton, D.L.; Grogan, J.L. The immunoreceptor TIGIT regulates antitumor and antiviral CD8(+) T cell effector function. Cancer Cell, 2014, 26(6), 923-937.
[http://dx.doi.org/10.1016/j.ccell.2014.10.018] [PMID: 25465800]
[9]
Stengel, K.F.; Harden-Bowles, K.; Yu, X.; Rouge, L.; Yin, J.; Comps-Agrar, L.; Wiesmann, C.; Bazan, J.F.; Eaton, D.L.; Grogan, J.L. Struc-ture of TIGIT immunoreceptor bound to poliovirus receptor reveals a cell-cell adhesion and signaling mechanism that requires cis-trans receptor clustering. Proc. Natl. Acad. Sci. USA, 2012, 109(14), 5399-5404.
[http://dx.doi.org/10.1073/pnas.1120606109] [PMID: 22421438]
[10]
Wu, L.; Mao, L.; Liu, J.F.; Chen, L.; Yu, G.T.; Yang, L.L.; Wu, H.; Bu, L.L.; Kulkarni, A.B.; Zhang, W.F.; Sun, Z.J. Blockade of TIG-IT/CD155 signaling reverses t-cell exhaustion and enhances antitumor capability in head and neck squamous cell carcinoma. Cancer Immunol. Res., 2019, 7(10), 1700-1713.
[http://dx.doi.org/10.1158/2326-6066.CIR-18-0725] [PMID: 31387897]
[11]
He, W.; Zhang, H.; Han, F.; Chen, X.; Lin, R.; Wang, W.; Qiu, H.; Zhuang, Z.; Liao, Q.; Zhang, W.; Cai, Q.; Cui, Y.; Jiang, W.; Wang, H.; Ke, Z. CD155T/TIGIT signaling regulates CD8+ T-cell metabolism and promotes tumor progression in human gastric cancer. Cancer Res., 2017, 77(22), 6375-6388.
[http://dx.doi.org/10.1158/0008-5472.CAN-17-0381] [PMID: 28883004]
[12]
Buyyounouski, M.; Choyke, P.; McKenney, J.; Sartor, O.; Sandler, H.; Amin, M.; Kattan, M.; Lin, D. Prostate cancer - major changesin the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J. Clin, 2017, 67(3), 245-253.
[13]
Subramanian, A.; Tamayo, P.; Mootha, V.K.; Mukherjee, S.; Ebert, B.L.; Gillette, M.A.; Paulovich, A.; Pomeroy, S.L.; Golub, T.R.; Lander, E.S.; Mesirov, J.P. Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl. Acad. Sci. USA, 2005, 102(43), 15545-15550.
[http://dx.doi.org/10.1073/pnas.0506580102] [PMID: 16199517]
[14]
Dougall, W.C.; Kurtulus, S.; Smyth, M.J.; Anderson, A.C. TIGIT and CD96: New checkpoint receptor targets for cancer immunotherapy. Immunol. Rev., 2017, 276(1), 112-120.
[http://dx.doi.org/10.1111/imr.12518] [PMID: 28258695]
[15]
Elashi, A.A.; Sasidharan Nair, V.; Taha, R.Z.; Shaath, H.; Elkord, E. DNA methylation of immune checkpoints in the peripheral blood of breast and colorectal cancer patients. OncoImmunology, 2018, 8(2), e1542918.
[http://dx.doi.org/10.1080/2162402X.2018.1542918] [PMID: 30713804]
[16]
Zhang, Q.; Bi, J.; Zheng, X.; Chen, Y.; Wang, H.; Wu, W.; Wang, Z.; Wu, Q.; Peng, H.; Wei, H.; Sun, R.; Tian, Z. Blockade of the check-point receptor TIGIT prevents NK cell exhaustion and elicits potent anti-tumor immunity. Nat. Immunol., 2018, 19(7), 723-732.
[http://dx.doi.org/10.1038/s41590-018-0132-0] [PMID: 29915296]
[17]
Zhang, C.; Wang, Y.; Xun, X.; Wang, S.; Xiang, X.; Hu, S.; Cheng, Q.; Guo, J.; Li, Z.; Zhu, J. TIGIT can exert immunosuppressive effects on CD8+ T Cells by the CD155/TIGIT signaling pathway for hepatocellular carcinoma in vitro. J. Immunother. (Hagerstown, Md. : 1997),, 2020, 43(8), 236-243.
[18]
Liu, X.G.; Hou, M.; Liu, Y. TIGIT, a novel therapeutic target for tumor immunotherapy. Immunol. Invest., 2017, 46(2), 172-182.
[http://dx.doi.org/10.1080/08820139.2016.1237524] [PMID: 27819527]
[19]
Manieri, N.A.; Chiang, E.Y.; Grogan, J.L. TIGIT: A key inhibitor of the cancer immunity cycle. Trends Immunol., 2017, 38(1), 20-28.
[http://dx.doi.org/10.1016/j.it.2016.10.002] [PMID: 27793572]
[20]
Pauken, K.E.; Wherry, E.J. TIGIT and CD226: Tipping the balance between costimulatory and coinhibitory molecules to augment the cancer immunotherapy toolkit. Cancer Cell, 2014, 26(6), 785-787.
[http://dx.doi.org/10.1016/j.ccell.2014.11.016] [PMID: 25490444]
[21]
Blake, S.J.; Dougall, W.C.; Miles, J.J.; Teng, M.W.; Smyth, M.J. Molecular pathways: Targeting CD96 and TIGIT for cancer immunothera-py. Clin. Cancer Res., 2016, 22(21), 5183-5188.
[http://dx.doi.org/10.1158/1078-0432.CCR-16-0933] [PMID: 27620276]
[22]
Sarhan, D.; Cichocki, F.; Zhang, B.; Yingst, A.; Spellman, S.R.; Cooley, S.; Verneris, M.R.; Blazar, B.R.; Miller, J.S.; Adaptive, N.K. Adap-tive NK cells with low tigit expression are inherently resistant to myeloid-derived suppressor cells. Cancer Res., 2016, 76(19), 5696-5706.
[http://dx.doi.org/10.1158/0008-5472.CAN-16-0839] [PMID: 27503932]
[23]
Xu, F.; Sunderland, A.; Zhou, Y.; Schulick, R.D.; Edil, B.H.; Zhu, Y. Blockade of CD112R and TIGIT signaling sensitizes human natural killer cell functions. Cancer Immunol. Immunother., 2017, 66(10), 1367-1375.
[http://dx.doi.org/10.1007/s00262-017-2031-x] [PMID: 28623459]
[24]
Chan, I.S.; Knútsdóttir, H.; Ramakrishnan, G.; Padmanaban, V.; Warrier, M.; Ramirez, J.C.; Dunworth, M.; Zhang, H.; Jaffee, E.M.; Bader, J.S.; Ewald, A.J. Cancer cells educate natural killer cells to a metastasis-promoting cell state. J. Cell Biol., 2020, 219(9), e202001134.
[http://dx.doi.org/10.1083/jcb.202001134] [PMID: 32645139]
[25]
Chauvin, J.M.; Zarour, H.M. TIGIT in cancer immunotherapy. J. Immunother. Cancer, 2020, 8(2), e000957.
[http://dx.doi.org/10.1136/jitc-2020-000957] [PMID: 32900861]
[26]
Ge, Z.; Peppelenbosch, M.P.; Sprengers, D.; Kwekkeboom, J. TIGIT, the next step towards successful combination immune checkpoint therapy in cancer. Front. Immunol., 2021, 12, 699895.
[http://dx.doi.org/10.3389/fimmu.2021.699895] [PMID: 34367161]
[27]
Bi, J.; Zheng, X.; Chen, Y.; Wei, H.; Sun, R.; Tian, Z. TIGIT safeguards liver regeneration through regulating natural killer cell-hepatocyte crosstalk. Hepatology, 2014, 60(4), 1389-1398.
[http://dx.doi.org/10.1002/hep.27245] [PMID: 24912841]
[28]
Fang, J.; Chen, F.; Liu, D.; Gu, F.; Chen, Z.; Wang, Y. Prognostic value of immune checkpoint molecules in breast cancer. Biosci. Rep., 2020, 40(7), BSR20201054.
[http://dx.doi.org/10.1042/BSR20201054] [PMID: 32602545]
[29]
Budczies, J.; Bockmayr, M.; Denkert, C.; Klauschen, F.; Lennerz, J.K.; Györffy, B.; Dietel, M.; Loibl, S.; Weichert, W.; Stenzinger, A. Classical pathology and mutational load of breast cancer - integration of two worlds. J. Pathol. Clin. Res., 2015, 1(4), 225-238.
[http://dx.doi.org/10.1002/cjp2.25] [PMID: 27499907]
[30]
Savas, P.; Virassamy, B.; Ye, C.; Salim, A.; Mintoff, C.P.; Caramia, F.; Salgado, R.; Byrne, D.J.; Teo, Z.L.; Dushyanthen, S.; Byrne, A.; Wein, L.; Luen, S.J.; Poliness, C.; Nightingale, S.S.; Skandarajah, A.S.; Gyorki, D.E.; Thornton, C.M.; Beavis, P.A.; Fox, S.B.; Darcy, P.K.; Speed, T.P.; Mackay, L.K.; Neeson, P.J.; Loi, S. Publisher Correction: Single-cell profiling of breast cancer T cells reveals a tissue-resident memory subset associated with improved prognosis. Nat. Med., 2018, 24(12), 1941.
[http://dx.doi.org/10.1038/s41591-018-0176-6] [PMID: 30135555]
[31]
Molfetta, R.; Zitti, B.; Lecce, M.; Milito, N.D.; Stabile, H.; Fionda, C.; Cippitelli, M.; Gismondi, A.; Santoni, A.; Paolini, R. CD155: A mul-ti-functional molecule in tumor progression. Int. J. Mol. Sci., 2020, 21(3), E922.
[http://dx.doi.org/10.3390/ijms21030922] [PMID: 32019260]
[32]
Pauken, K.E.; Wherry, E.J. Overcoming T cell exhaustion in infection and cancer. Trends Immunol., 2015, 36(4), 265-276.
[http://dx.doi.org/10.1016/j.it.2015.02.008] [PMID: 25797516]

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